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Quality assurance for aseptic production


Farshid Sadeghipour
Head of Production

Pascal Bonnabry
Director of Pharmacy
Department of Pharmacy
University Hospitals of Geneva (HUG)
E:[email protected]

The current trend is for the aseptic preparation of sterilised drugs to be carried out in hospital pharmacies.(1,2) Many hospitals are gradually abandoning their sterilised production line for a redeployment of resources in aseptic manufacturing (see Figure 1). There is a need for individualised ready-to-use injectables, such as paediatric parenteral nutrition, antibiotics, cytostatic drugs or intensive care pharmaceuticals,(3,4) and many hospital pharmacies have developed their aseptic production units considerably to improve the safety of injectable drugs, thus offering better quality assurance compared with preparations in wards.(5)


Whereas for sterilised drugs a complete physicochemical and sterility testing, carried out in the quality control laboratory, ensures the final quality of the product, no final quality control is possible for ready-to-use drugs, which are manufactured individually in aseptic conditions. Risk assessment is therefore based on the quality assurance system built around the production procedures of these drugs. This quality assurance network is based on three main principles:

  • Documented procedures, protocols and equipment.
  • Quality control of the production environment.
  • Qualification of the operators (see Table 1).


GMP and aseptic production
Generally, the aseptic production follows the good manufacturing practice (GMP), specifically its Annex on sterile products.(6) Even if these guidelines are intended for industrial production, the main points can be applied to preparation in hospital pharmacies. In the past few years, similar guidelines for hospital pharmacy have been published,(7) taking into account the particularities of aseptic production in this context.

All guidelines request special awareness of:

  • Building and facilities, especially the cleanroom and its filtration system.
  • Staff training, qualification and monitoring.
  • Validation of aseptic processing.
  • Laboratory controls, mostly for cleanroom environment monitoring and control of sanitisation efficiency.
  • Documentation, consisting of protocols and standard operating procedures (SOPs) for both production/ quality control and efficient traceability, from raw materials to final products.

Documented procedures and protocols
A structured and comprehensive documentation, including written and approved SOPs for all the critical processes, especially aseptic preparation, is needed. Simple and understandable procedures must be edited for routine operations such as gowning of the operators in the cleanroom. Different qualifications and validations have to be performed on the basis of written protocols, and all the results have to be fully documented. It is important to transcribe every step of every preparation to standardise daily manipulations as much as possible. To summarise, every operation has to be written, approved and traceable at any time.

Moreover, the use of a prospective systematic risk analysis method helps improve the security of a production procedure (see Resource).(8,9) It underlines the weak points and allows the comparison of different process options, so that the most appropriate can be selected.

Quality control of the production environment and equipment
For aseptic production, the principal equipment is the cleanroom and the laminar airflow hoods (or isolators) installed inside. Initial qualifications of the cleanroom design and filtration system are mandatory. The cleaning and sanitisation of the controlled environment and the validation of its efficiency have become major GMP topics. Routine monitoring of viable and nonviable particle contamination is a necessary task of the quality control laboratory. In addition, microbiological in-process controls, such as settle plates and glove fingerprints, ensure the sterility of the preparation background atmosphere. Discussing monitoring results with operators is of great value, as it involves them in the improvement of the cleanroom quality control.

The use of positive and negative pressure isolators to manufacture nontoxic and cytotoxic drugs improves security for both operator and product.(10) However, the isolator must be subjected to a complete installation, and to operational and performance qualifications, as for each piece of equipment. Performance qualification mainly involves the microbiological validation of the drug preparation procedures, but it can also involve the sterilisation process.

Qualification of the operators
Qualification of the operators should be the result of structured teaching and continuous training in aseptic techniques. Operators need to be trained both  theoretically and practically. Each training session should be documented, with a new session being scheduled at the end of each “lesson”. It is important to keep a training logbook for every operator.

Process simulation techniques, such as media fill trials (MFTs), simultaneously allow the qualification of the manufacturing process and the validation of the operators’ acquired competencies.(11,12) Specific MFT protocols must be adapted to routine procedures, including “worst-case” situations. Regular qualification of the operators ensures the quality assurance system.

Additional qualification of the working conditions using spillage quantification with a tracer (eg, (99m)Tc) improves risk control.(13) All these qualifications emphasise the operator’s awareness of the different risks inherent in aseptic production.

The quality assurance programme established for each hospital pharmacy must be a long-term programme. The important point is not necessarily to be up-to-date and totally in accordance with the highest GMP standards, but to follow a positive trend towards higher quality at each step. This evolution can be achieved within the limits of the financial and the human resources specific to each aseptic service. Nevertheless, quality requirements are becoming increasingly challenging, and although specific hospital pharmacy GMPs noticeably restrain our margin of action, they also lead to faster compliance with the rules.
The aim of GMPs is to ensure the best security and quality for the patient, and, in the case of aseptically manufactured drugs, to ensure that the label “sterile” is not misapplied.


  1. Am J Health-Syst Pharm 1996;53:591-605.
  2. Hosp Pharm 2003;10:306-8.
  3. Hosp Pharm Eur 2003;10:78-80.
  4. J Parenter Enteral Nutr 2003;27:433-8.
  5. J Hosp Infect 2004;56:79-81.
  6. Manufacture of sterile medicinal products. EC Guide to Good Manufacturing Practice, Annex 1. Brussels (EU): European Commission; 2003. p. 3-5.
  7. Bonnes pratiques de préparation à l’Hôpital, Projet, 15 juillet 2002, Agence française de sécurité sanitaire des produits de santé.
  8. Therapie 2001;56:525-31.
  9. J Eval Clin Pract 1997;3:213-22.
  10. Am J Health-Syst Pharm 1999;56:1433-6.
  11. STP Pharma Pratiques 1998;8:18-26 .
  12. J Pharm Sci Technol 1998;52 Suppl:1-15.
  13. Eur J Hosp Pharm 2004;3:40-2.

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